Drug Safety


Clinical Trial Safety – The Goldilocks Dilemma – Balancing Effective and Efficient Safety Monitoring


Jonathan Seltzer President, Applied Clinical Intelligence, and Director, Clinical Research, Main Line Health Heart Center


Abstract


Clinical trial safety monitoring is an important and expensive responsibility. Using a risk-based analysis to inform clinical safety monitoring, programmes can promote improved safety monitoring while simultaneously improving efficiencies. This article suggests a framework for evaluating the major patient-, compound-, intervention-, operation- and communication-based risk factors that affect clinical trial safety. The article suggests that, through the use of such an analysis, optimal safety monitoring plans can be generated. In addition, the article reviews some safety tools and suggests how they may be used to improve efficiency.


Keywords Clinical trial safety, data safety monitoring, clinical monitoring, safety monitoring plan


Disclosure: Jonathan Seltzer is a shareholder and employee of Applied Clinical Intelligence (ACI). ACI provides safety consulting and expert safety committees to commercial and not-for-profit sponsors. Acknowledgements: The author would like to thank Jing Jin for her help in the preparation of this article. Received: 23 September 2010 Accepted: 15 November 2010 Citation: Drug Development, 2010;5:8–11 Correspondence: Jonathan Seltzer, President, Applied Clinical Intelligence, Director, Clinical Research, Main Line Health Heart Center, 225 City Avenue, Suite 15, Bala Cynwyd, PA 19004, US. E: jseltzer@a-ci.com


Goldilocks sought porridge that was neither too hot nor too cold; a chair neither too big nor too small; and a bed neither too hard nor too soft. She wanted everything ‘just right’. When implementing a strategy for clinical trial safety monitoring, the Goldilocks’ principle of ‘just right’ should be applied. Clinical trial safety requires subjects to be neither overtested nor undertested; data collection neither incomplete nor too complex; and investigators and safety monitors neither too constrained nor too uncontrolled. In the current era of drug development, when it comes to managing clinical trial safety, just right means more than regulatory compliance. In fact, it has been noted that the focus on reporting compliance may even obscure a true safety signal.1


So, how does one develop and implement a clinical trial safety plan that ensures safety without unnecessary expense or patient burden? The thinking of management guru Peter Drucker may be of help in approaching this issue. Drucker is widely attributed as saying: “Efficiency is doing things right; effectiveness is doing the right things.”


Application of Drucker’s maxim to clinical trial safety implies that the crucial first step is deciding on effective safety monitoring (defined as the proper type and amount of surveillance). This needs to be followed by a focus on efficient safety monitoring (defined by implementing the proper type and amount of surveillance in the most cost-effective manner).


Effective Safety Monitoring


Development of effective safety monitoring requires more than the risk mitigation strategies outlined in regulatory guidelines. Often, the


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As an example, if the compound is thought to be relatively safe, but has complex storage handling and preparation requirements it is


© TOUCH BRIEFINGS 2010


guidelines are based upon physiological factors, such as surveillance strategies for liver function tests, QT intervals and, most recently, suicidality;2–4


however, there are other factors that must be considered.


In addition, today’s rapidly changing technological and political/economic environment requires assessment of the impact of clinical operations and clinical communication risk factors.


Recently, an elegant new model for assessment has been developed and is undergoing testing for intervention- and trial-specific risk factors.5


A multipronged risk-analysis approach should therefore be taken in order to implement an effective safety monitoring approach. This approach, at a minimum, should include the following types of assessments:


• compound- or intervention-based risk factors (see Table 1);


• patient-based risk factors (see Table 2); • operation-based risk factors (see Table 3); and • communication-based risk factors (see Table 4).


Compound- or Intervention-based Risk Factors Compound- or intervention-based risk factors usually make up the bulk of standard safety decisions. Regulatory documents require this information and suggest it forms the basis of risk-mitigation activities. Some factors that are important to consider/address when creating an effective safety monitoring plan are detailed in Table 1.


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